The present invention is directed to a process for the efficient solution and solid-phase synthesis of Boc-protected 3-aminohydantoins/thiohydantoins and 3-aminodihydrouracils/dihydrothiouracils.
The present invention is directed to a novel process for synthesizing Boc-protected 3-aminohydantoins, 3-aminodihydrouracils, and their thio-substituted counterparts using a one-pot solution-phase or solid-phase process. 3-aminohydantoin and 3-aminodihydrouracil derivatives are useful in both the pharmaceutical and agrochemical industries. For example, compounds containing the 3-aminohydantoin or 3-aminodihydrouracil nucleus are useful as anticonvulsant agents, antibacterial agents, metalloprotease inhibitors, diuretic agents, and pesticides.
Synthetic routes for the preparation of 3-aminohydantoin derivatives are disclosed in the following references: Kiec-Kononowicz, K.; Zejc, A.; Byrtus, H. Pol. J. Chem. 1984, 58, 585. Lange, J. et al. Polish Patent, PL 123138 B1, Apr. 30, 1984. Wright, G. C.; Michels, J. G.; Spencer, C. F. J. Med. Chem. 1969, 12, 379-381. Bernard, L. et al. French Patent, 2000801, Jan. 24, 1969. Kobayashi, N. et al. Japanese Patent, 09176131 A2, Jul. 8, 1997. Taub, W. U.S. Pat. No. 2,767,193, 1956. Chem. Abstr., 1957, 51, 5811. Szczepanski, H.; Kristinsson, H.; Maienfish, P.; Ehrenfreund, J. WO 95/18123, 1995. Lindemann, A.; Khan, N. H.; Hoffmann, K. J. Am. Chem. Soc., 1952, 74, 476-479. Gante, J.; Lautsch, W. Chem. Ber., 1964, 97, 994. Schlogl, K.; Derkosch, J.; Korger, G. C. Monatsh. Chem. 1954, 85, 607. Schlogl, K.; Korger, G. Monatsh. Chem. 1951, 82, 799. Davidson, J. S. J. Chem. Soc. 1964, 4646-4647. Gillis, B. T.; Dain, J. G. J. Heterocyclic Chem. 1971, 8, 339-339. Wildonger, R. A; Winstead, M. B. J. Heterocyclic Chem. 1967, 4, 981-982. Lalezari, I. J. Heterocyclic Chem. 1985, 22, 741-743. Saegusa, Y.; Harada, S.; Nakamura, S. J. Heterocyclic Chem. 1990, 27, 739-742. Milcent, R.; Akhnazarian, A.; Lensen, N. J. Heterocyclic Chem. 1996, 33, 1829-1833. Ragab, F. A.; Eid, N. M.; El-Tawab, H. A. Pharmazie 1997, 52 (12), 926-929. Yoon, J; Cho, C-W; Han; H; Janda, K. D. Chem. Comm. 1998, 2703-2704. However, in general the synthetic routes disclosed above involve multiple steps, require harsh reaction conditions, and/or produce relatively low yields.
Additionally, there has been growing interest in the development of solid-phase synthetic approaches to hydantoin and dihydrouracil derivatives, particularly those substituted at the N-1, N-3, and C-5 positions. Syntheses of 1-aminohydantoins and 3-aminohydantoins by solid-phase synthetic approaches are disclosed in the following references: Dewitt, S. H.; Kiely, J. S.; Stankovic, C. J.; Schroder, M. C.; Reynolds Cody, D. M.; Pavia, M. R. Proc. Natl. Acad. Sci. 1993, 90, 6909-6913. Dressman, B. A.; Spangle, L. A.; Kaldor, S. W. Tetrahedron Lett. 1996, 37, 937-940. Hanessisan, S.; Yany, R.-Y. Tetrahedron Lett. 1996, 37, 5835-5838. Kim, S. W.; Ahn, S. Y.; Koh, J. S.; Lee, J. H.; Ro, S.; Cho, H. Y. Tetrahedron Lett. 1997, 38, 4603-4606. Matthews, J.; Rivero, R. A. J. Org. Chem. 1997, 62, 6090-6092. Gong, Y-D.; Najdi, S.; Olmstead, M. M.; Kurth, M. J. J. Org. Chem. 1998, 63, 3081-3086. Xiao, X.; Ngu, K.; Chao, C.; Patel, D. V. J. Org. Chem. 1997, 62, 6968-6973. Smith, J.; Liras, J. L.; Schneider, S. E.; Anslyn, E. V. J. J. Org. Chem. 1996, 61, 8811-8813. Sim, M. M.; Ganesan, A. J. Org. Chem. 1997, 62, 3230-3233. Wilson, L. J.; Li, M.; Portlock, D. E. Tetrahedron Lett. 1998, 39, 5135-5138. Hamuro, Y.; Marshall, W. J.; Scialdone, M. A. J. Comb. Chem. 1999, 1, 163-167.
There is a continuing need for improved processes for producing 3-aminohydantoins, 3-aminodihydrouracils, and their thio-substituted counterparts.
The present invention provides a process for the efficient assembly of Boc-protected 3-aminohydantoins/thiohydantoins and 3-aminodihydrouracils/dihydrothiouracils via a one-pot solution phase or solid phase synthesis from readily available starting materials.
Definitions and Usage of Terms
xe2x80x9cAlkylxe2x80x9d is a saturated or unsaturated hydrocarbon chain having 1 to 18 carbon atoms, preferably 1 to 12, more preferably 1 to 6, more preferably still 1 to 4 carbon atoms. Alkyl chains may be straight or branched. Preferred branched alkyl have one or two branches. Unsaturated alkyl have one or more double bonds and/or one or more triple bonds. Alkyl chains may be unsubstituted or substituted with from 1 to about 4 substituents unless otherwise specified.
xe2x80x9cAromatic ringxe2x80x9d is a benzene ring or a naphthlene ring.
xe2x80x9cCarbocyclic ringxe2x80x9d is a saturated or unsaturated hydrocarbon ring. Carbocyclic rings are not aromatic. Carbocyclic rings are monocyclic, or are fused, spiro, or bridged bicyclic ring systems. Monocyclic carbocyclic rings contain from about 4 to about 10 carbon atoms, preferably from 4 to 7 carbon atoms, and most preferably from 5 to 6 carbon atoms in the ring. Bicyclic carbocyclic rings contain from 8 to 12 carbon atoms, preferably from 9 to 10 carbon atoms in the ring. Carbocyclic rings may be unsubstituted or substituted with from 1 to about 4 substituents on the ring.
xe2x80x9cHeteroatomxe2x80x9d is a nitrogen, sulfur, or oxygen atom. Groups containing more than one heteroatom may contain different heteroatoms. As used herein, halogens are not heteroatoms.
xe2x80x9cHeterocyclic ringxe2x80x9d is a saturated or unsaturated ring containing carbon and from 1 to about 4 heteroatoms in the ring. Heterocyclic rings are not aromatic. Heterocyclic rings are monocyclic, or are fused or bridged bicyclic ring systems. Monocyclic heterocyclic rings contain from about 4 to about 10 member atoms (carbon and heteroatoms), preferably from 4 to 7, and most preferably from 5 to 6 member atoms in the ring. Bicyclic heterocyclic rings contain from 8 to 12 member atoms, preferably 9 or 10 member atoms in the ring. Heterocyclic rings may be unsubstituted or substituted with from 1 to about 4 substituents on the ring.
xe2x80x9cHeteroaromatic ringxe2x80x9d is an aromatic ring system containing carbon and from 1 to about 4 heteroatoms in the ring. Heteroaromatic rings are monocyclic or fused bicyclic ring systems. Monocyclic heteroaromatic rings contain from about 5 to about 10 member atoms (carbon and heteroatoms), preferably from 5 to 7, and most preferably from 5 to 6 in the ring. Bicyclic heteroaromatic rings contain from 8 to 12 member atoms, preferably 9 or 10 member atoms in the ring. Bicyclic heteroaromatic rings are ring systems wherein at least one of the two rings is a heteroaromatic ring and the other ring is a heteroaromatic ring, an aromatic ring, a carbocyclic ring, or a heterocyclic ring. Heteroaromatic rings may be unsubstituted or substituted with from 1 to about 4 substituents on the ring.
xe2x80x9cMember atomxe2x80x9d refers to a polyvalent atom (C, O, N, or S atom) in a chain or ring system that continues the chain or ring system. For example, in benzene the six carbon atoms are member atoms and the six hydrogen atoms are not member atoms.
Compounds Prepared Using the Present Process
The present invention is directed to a one-pot, solution-phase process for making Boc-protected 3-aminohydantoins/thiohydantoins and 3-aminodihydrouracils/dihydrothiouracils according to Formula I below: 
In Formula I above, X is O or S.
In Formula I above, n is 0 or 1.
In Formula I above, R1 is H, alkyl, carbocyclic ring, heterocyclic ring, aromatic ring, or heteroaromatic ring. When R1 is substituted alkyl, preferred substituents include: halo, hydroxy, alkoxy, aryloxy, acyloxy, carboxy, mercapto, alkylthio, arylthio, acylthio, carbamoyl, amido, aromatic ring, heteroaromatic ring, carbocyclic ring, and heterocyclic ring.
In Formula I above, R2 is H, alkyl, carbocyclic ring, heterocyclic ring, aromatic ring, or heteroaromatic ring. When R2 is substituted alkyl, preferred substituents include: halo, hydroxy, alkoxy, aryloxy, acyloxy, carboxy, alkoxycarbonyl, mercapto, alkylthio, arylthio, acylthio, amino, carbamoyl, carbamoyloxy, amido, alkoxylamido, ureido, guanidino, aryl, heteroaryl, cycloalkyl or heterocyclyl.
In Formula I above, when n is 0, R1 and R2 may instead together form a ring system; said ring system being carbocyclic ring, heterocyclic ring, or heteroaromatic ring. When n is 1, R1 and the member carbon atom adjacent to the carbon atom containing R2 may instead together form a ring system; said ring system being carbocyclic ring, heterocyclic ring, or heteroaromatic ring.
The Boc-protected 3-aminohydantoins/thiohydantoins and 3-aminodihydrouracils/dihydrothiouracils of the present invention may be further modified into substituted 3-aminohydantoins/thiohydantoins and 3-aminodihydrouracils/dihydrothiouracils using methods known to one of ordinary skill in the art.
Compounds which may be prepared using the present invention include, but are not limited to the following:
Carbamic acid, [2,5-dioxo-3-(phenylmethyl)-1-imidazolidinyl]-, 1,1-dimethylethyl ester. 
Carbamic acid, [5-oxo-3-(phenylmethyl)-2-thioxo-1-imidazolidinyl]-, 1,1-dimethylethyl ester. 
Carbamic acid, [4-methyl-2,5-dioxo-3-(phenylmethyl)-1-imidazolidinyl]-, 1,1-dimethylethyl ester. 
Carbamic acid, [4-methyl-5-oxo-3-(phenylmethyl)-2-thioxo-1-imidazolidinyl]-, 1,1-dimethylethyl ester. 
Carbamic acid, ((7aS)-tetrahydro-1,3-dioxo-1H-pyrrolo[1,2-c]imidazol-2(3H)-yl-, 1,1-dimethylethyl ester. 
Carbamic acid, ((7aS)-tetrahydro-1-oxo-3-thioxo-1H-pyrrolo[1,2-c]imidazol-2(3H)-yl-, 1,1-dimethylethyl ester. 
Carbamic acid, (Hexahydro-1,3-dioxoimidazol[1,5-a]pyridin-2(3H)-yl)-, 1,1-dimethylethyl ester. 
Carbamic acid, (Hexahydro-1-oxo-3-thioxoimidazol[1,5-a]pyridin-2(3H)-yl)-, 1,1-dimethylethyl ester. 
Carbamic acid, ((10aS)-1,5,10,10a-tetrahydro-1,3-dioxoimidazol[1,5-b]isoquinolin-2(3H)-yl)-, 1,1-dimethylethyl ester. 
Carbamic acid, ((10aS)-1,5,10,10a-tetrahydro-1-oxo-3-thioxoimidazol[1,5-b]isoquinolin-2(3H)-yl)-, 1,1-dimethylethyl ester. 
Carbamic acid, (Tetrahydro-5,7-dioxoimidazol[5,1-b]thiazol-6(5H)-yl)-, 1,1-dimethylethyl ester. 
Carbamic acid, (Tetrahydro-7-oxo-7-thioxoimidazol[5,1-b]thiazol-6(5H)-yl)-, 1,1-dimethylethyl ester. 
Carbamic acid, ((6R,7aS)-tetrahydro-6-hydroxy-1,3-dioxo-1H-pyrrolo[1,2-c]imidazol-2(3H)-yl-, 1,1-dimethylethyl ester. 
Carbamic acid, (2,5-dioxo-3-phenyl-1-imidazolidinyl)-, 1,1-dimethylethyl ester. 
Carbamic acid, (5-oxo-3-phenyl-2-thioxo-1-imidazolidinyl)-, 1,1-dimethylethyl ester. 
Carbamic acid, (tetrahydro-2,6-dioxo-3-(phenylmethyl)-1(2H)-pyrimidinyl)-, 1,1-dimethylethyl ester. 
Carbamic acid, (tetrahydro-6-oxo-3-(phenylmethyl)-2-thioxo-1(2H)-pyrimidinyl)-, 1,1-dimethylethyl ester. 
Carbamic acid, (3-(2-furanylmethyl)tetrahydro-2,6-dioxo-1(2H)-pyrimidinyl)-, 1,1-dimethylethyl ester. 
Carbamic acid, (3-(2-furanylmethyl)tetrahydro-6-oxo-2-thioxo-1(2H)-pyrimidinyl, 1,1-dimethylethyl ester. 
Carbamic acid, (3-butyltetrahydro-2,6-dioxo-1(2H)-pyrimidinyl)-, 1,1-dimethylethyl ester. 
Carbamic acid, (3-butyltetrahydro-6-oxo-2-thioxo-1(2H)-pyrimidinyl-, 1,1-dimethylethyl ester. 
Carbamic acid, (tetrahydro-6-oxo-3-phenyl-2-thioxo-1(2H)-pyrimidinyl)-, 1,1-dimethylethyl ester. 
Carbamic acid, (tetrahydro-6-oxo-3-(4-methoxyphenyl)-2-thioxo-1(2H)-pyrimidinyl)-, 1,1-dimethylethyl ester. 
Carbamic acid, (hexahydro-1,6,8-trioxo-2H-pyrazino[1,2-c]pyrimidin-7(6H)-yl-, 1,1-dimethylethyl ester. 
Carbamic acid, [3-[(4-methoxyphenyl)methyl)-2,5-dioxo-1-imidazolidinyl]-, 1,1-dimethylethyl ester. 
Carbamic acid, [3-(1,3-benzodioxol-5-ylmethyl)-2,5-dioxo-1-imidazolidinyl]-, 1,1-dimethylethyl ester. 
Carbamic acid, [2,5-dioxo-3-[2-(2-pyridinyl)ethyl]-1-imidazolidinyl]-, 1,1-dimethylethyl ester. 
Carbamic acid, [3-[2-(5-methoxy-1H-indol-3-yl)ethyl]-2,5-dioxo-1-imidazolidinyl]-, 1,1-dimethylethyl ester. 
Carbamic acid, [3-[2-(1H-imidazol-4-yl)-ethyl]-2,5-dioxo-1-imidazolidinyl]-, 1,1-dimethylethyl ester. 
Carbamic acid, [3-[2-(1H-imidazol-1-yl)-ethyl]-2,5-dioxo-1-imidazolidinyl]-, 1,1-dimethylethyl ester. 
Carbamic acid, [3-[2-[[5-nitro-2-pyridinyl]amino]ethyl]-2,5-dioxo-1-imidazolidinyl]-, 1,1-dimethylethyl ester. 
Carbamic acid, [2,5-dioxo-3-[2-(1-piperidinyl)ethyl]-1-imidazolidinyl)-, 1,1-dimethylethyl ester. 
Carbamic acid, [5-oxo-3-[2-(1-piperidinyl)ethyl]-2-thioxo-1-imidazolidinyl]-, 1,1-dimethylethyl ester. 
Carbamic acid, [3-[2-(1-methyl-2-pyrrolidinyl)ethyl]-2,5-dioxo-1-imidazolidinyl]-, 1,1-dimethylethyl ester. 
Carbamic acid, [3-[2-(2-methyl-1-piperidinyl)propyl]-2,5-dioxo-1-imidazolidinyl]-, 1,1-dimethylethyl ester. 
Carbamic acid, [2,5-dioxo-3-[3-(1-piperidinyl)propyl]-1-imidazolidinyl]-, 1,1-dimethylethyl ester. 
Carbamic acid, [3-[3-(4-morpholinyl)propyl]-2,5-dioxo-1-imidazolidinyl]-, 1,1-dimethylethyl ester. 
Carbamic acid, [2,5-dioxo-3-[3-(2-oxo-1-pyrrolidinyl)propyl]-1-imidazolidinyl]-, 1,1-dimethylethyl ester. 
Carbamic acid, (3-[(6,6-dimethylbicyclo[3.1.1]hept-3-yl)methyl]-2,5-dioxo-1-imidazolidinyl]-, 1,1-dimethylethyl ester. 
Carbamic acid, [2,5-dioxo-3-[1-(phenylmethyl)-4-piperidinyl]-1-imidazolidinyl]-, 1,1-dimethylethyl ester. 
Carbamic acid, [3-[(4-methoxyphenyl)methyl)-5-oxo-2-thioxo-1-imidazolidinyl]-, 1,1-dimethylethyl ester. 
Carbamic acid, [tetrahydro-3-[(5-nitro-2-pyridinyl)amino]ethyl]-2,6-dioxo-1(2H)-pyrimidinyl]-, 1,1-dimethylethyl ester. 
Carbamic acid, [tetrahydro-3-[2-(4-morpholinyl)ethyl]-2,6-dioxo-1(2H)-pyrimidinyl]-, 1,1-dimethylethyl ester. 
Carbamic acid, [tetrahydro-2,6-dioxo-3-[1-(phenylmethyl)-4-piperidinyl]-1(2H)-pyrimidinyl]-, 1,1-dimethylethyl ester. 
Solution-Phase Process for Making Compounds According to Formula I
In one embodiment, the present invention provides a one-pot solution-phase process for preparing compounds according to Formula I above depicted below as Scheme I. The process depicted below in Scheme I requires no chromatographies (for n=0) and a simple liquid/liquid extraction and crystallization/filtration at the end. 
The process depicted above in Scheme I begins with providing a compound according to Formula II. In Formula II, X is as defined above for Formula I. Compounds according to Formula II can be made from known starting materials and methods known to one of ordinary skill in the art. One particularly preferred method for the preparation of compounds according to Formula II involves slow addition of commercially available t-butoxycarbonyl (Boc) hydrazine to carbonyldiimidazole (X=O) or thiocarbonyldiimidazole (X=S). Once made, compounds according to Formula II need not be isolated, but rather can be reacted in situ for the next step.
Compounds according to Formula II are first reacted with amino acid esters having the following general structure: 
wherein R1 and R2 are as defined above for Formula I, and R is alkyl, carbocyclic ring, heterocyclic ring, aromatic ring, or heteroaromatic ring. Preferred R is methyl, ethyl, and benzyl. These amino acid esters are commercially available or are made from commercially available starting materials from methods known to one of ordinary skill in the art.
The resulting intermediates according to Sia need not be isolated, but rather undergo intramolecular cyclization to the desired products of Formula I on warning. Thus, the next step in the process is heating the reaction mixture. The preferred reaction time is 8 hours and the reaction temperature is preferably kept between 60-70xc2x0 C. for 3-aminohydantoin derivatives (Formula I wherein n=0). The preferred reaction time is  greater than 24 hours and the reaction temperature is preferably kept between 100-110xc2x0 C. for 3-aminodihydrouracil derivatives (Formula I wherein n=1). Commonly used organic solvents are used. Preferred organic solvents include THF, DMF, dioxane, and methylene chloride. The most preferred organic solvent is dioxane.
Solid-Phase Process for Making Compounds According to Formula I
In another embodiment, the present invention provides a solid-phase process for preparing compounds according to Formula Ia below. Formula Ia is a subset of Formula I compounds. 
wherein
X is O or S;
n is 0 or 1;
R1a is H, alkyl, carbocyclic ring, heterocyclic ring, aromatic ring, or heteroaromatic ring;
R2a is H, alkyl, carbocyclic ring, heterocyclic ring, aromatic ring, or heteroaromatic ring;
The solid phase process is depicted below as Scheme II. 
The process depicted above in Scheme II begins with providing a compound according to Formula II. Compounds according to Formula II are first reacted with resin-bound or amino acid esters having the following general structure: 
wherein R1a and R2a are as defined above for Formula I, and 
is a Merrifield resin, hydroxymethyl resin, Wang resin, or PEG resin, preferably a Merrifield resin. These resin-bound or amino acid esters are made from commercially available starting materials from methods known to one of ordinary skill in the art. A preferred method for the preparation of Merrifield resin-bound or amino acid esters resins is to esterify the Merrifield resin with xcex1-bromoacetic acid or acrylic acid. Relevant references include: Wilson, L. J.; Li, M.; Portlock, D. E. Tetrahedron Lett. 1998, 39 5135-5138. Morphy, J. R.; Rankovic, Z.; Rees, D. C. Tetrahedron Lett. 1996, 37 3209-3212. Kolodziej, S.; Hamper, B. C. Tetrahedron Lett. 1996, 37 5277-5280.
Compounds according to Formula II are preferably reacted with these resin-bound or amino acid esters at room temperature. Intermediates according to Siia are then thoroughly washed to remove impurities and excess reagents. In this reaction step, common organic solvents are used. Preferred organic solvents include THF, DMF, dioxane, acetonitrile and methylene chloride. The most preferred solvent is anhydrous DMF.
Warming compounds according to Siia induces intramolecular cyclization and release from the resin to provide the desired products according to Formula I. Thus, the next step in the process is heating the reaction mixture. The temperature of the cyclization reaction is preferably kept between about 60-70xc2x0 C. and the reaction time is preferably about 8-10 hours for the formation of 3-aminohydantoin derivatives (Formula I, wherein n=0). The temperature of the cyclization reaction is preferably kept between about 90-95xc2x0 C. and the reaction time is preferably 24 hours for the formation of 3-aminodihydrouracil derivatives (Formula I, wherein n=1).
This method allows for the ready preparation of 3-aminohydantoins/thiohydantoins and 3-aminodihydrouracils/dihydrothiouracils which contain a wide variety of substituents at N-1, including basic groups which can be difficult to purify when made by solution methods.
The following non-limiting examples illustrate the present invention: